Compounds of formula (I) are known from the prior art as active substances for example for the treatment of diseases of the lungs and airways (J. Med. Chem. 49 (2006) 4098-4115). Processes for preparing compounds of formula (I) from compounds of formula (III) with Rt=methyl (Laeckmann, D. et al. Bioorg., Med. Chem. 10 (2002) 1793-1804) or from compounds of formula (IV) (J. Med. Chem. 49 (2006) 4098-4115) are known from the prior art. 2-Tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate (tert-butyl-methylisoxazolium perchlorate), also referred to as “Woodward's reagent L” is known from the prior art as an intermediate for the synthesis of compounds of formula (III) (Laeckmann, D. et al. Bioorg. Med. Chem. 10 (2002) 1793-1804). Due to the known oxidizing properties of the perchlorate ion, the use of tert-butyl-methylisoxazolium perchlorate may constitute a substantial hazard, especially when applied in larger scale. The “Recommendations on the transport of dangerous goods; Manual of Tests and Criteria (United Nations, 5th revised ed. 2010; appendix 6, page 440, Table A6.1)” list the perchlorate moiety as a group indicating explosive properties in organic materials. No salts of the 2-tert-butyl-5-methyl-1,2-oxazol-2-ium ion other than the perchlorate are known from the literature.
The preparation of compounds of formula (IV) from compounds of formula (III) is known from the prior art (Shepard, K. L. et al. J. Heterocyclic Chem. 13 (1976) 1219-1224). The preparation of compounds of formula (IV) from compounds of formula (V)R1—COOH  (V)without generating compounds of formula (III) as intermediates is described in WO2009074575. The reaction described therein requires the coupling reagent O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) which is regarded as a potential explosive.
The problem of the present invention is to provide a process, which avoids the use of highly hazardous intermediates or reagents, for preparing compounds of formula (I).
Especially the problem of the present invention is to provide a process, which avoids the use of highly hazardous intermediates, for preparing compounds of formula (III) or (IV).
Especially the problem of the present invention is to provide a process for preparing compounds of formula (I) without the use of 2-tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate, other perchlorate salts, perchloric acid, HATU, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) or other reagents based on 1-hydroxy-7-azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBT) or hydrogen sulphide. In order to avoid highly hazardous intermediates the exothermic decomposition energy of reagents and intermediates applied in the process should be less than 2000 J/g and the onset of exothermic decomposition (if applicable) should be above 180° C. (For comparison: Differential Scanning calorimetry data (Closed gold vessel) for 2-tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate (“Woodward's reagent L”): Exothermic event of ΔH=4395 J/g and Tonset=158° C.)